Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming

  • Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):24. doi: 10.1167/iovs.61.12.24.
Ji Yeon Do  1 ,  Juhee Kim  1 ,  Mi-Jin Kim  1 ,  Jung Yi Lee  1  2 ,  So-Young Park  3 ,  Ryoji Yanai  4 ,  In-Kyu Lee  1  5 ,  Sungmi Park  1 ,  Dong Ho Park  1  6
Affiliations
  • 1. Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Kyungpook National University, Daegu, Republic of Korea.
  • 2. R&D Center, JD Bioscience, Inc., Gwangju, Republic of Korea.
  • 3. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • 4. Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
  • 5. Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu, Republic of Korea.
  • 6. Department of Ophthalmology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu, Republic of Korea.
PMID: 33107903 DOI: 10.1167/iovs.61.12.24
Abstract

Purpose: To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE).

Methods: The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine.

Results: In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells.

Conclusions: Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

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